PUBLICATION
Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects
- Authors
- Runtuwene, V., van Eekelen, M., Overvoorde, J., Rehmann, H., Yntema, H.G., Nillesen, W.M., van Haeringen, A., van der Burgt, I., Burgering, B., and den Hertog, J.
- ID
- ZDB-PUB-110131-17
- Date
- 2011
- Source
- Disease models & mechanisms 4(3): 393-399 (Journal)
- Registered Authors
- den Hertog, Jeroen, Overvoorde, John
- Keywords
- none
- MeSH Terms
-
- Amino Acid Substitution
- Animals
- Base Sequence
- Cell Movement
- Craniofacial Abnormalities/embryology
- Craniofacial Abnormalities/metabolism
- Craniofacial Abnormalities/pathology
- Embryo, Nonmammalian/abnormalities
- Embryo, Nonmammalian/metabolism
- Embryo, Nonmammalian/pathology
- Gastrulation/genetics*
- Humans
- Molecular Sequence Data
- Mutation/genetics*
- Noonan Syndrome/genetics*
- Oncogene Proteins/genetics*
- Oncogene Proteins/metabolism
- Protein Transport
- Signal Transduction
- Zebrafish/embryology*
- Zebrafish/metabolism
- ras Proteins/genetics*
- ras Proteins/metabolism
- PubMed
- 21263000 Full text @ Dis. Model. Mech.
Citation
Runtuwene, V., van Eekelen, M., Overvoorde, J., Rehmann, H., Yntema, H.G., Nillesen, W.M., van Haeringen, A., van der Burgt, I., Burgering, B., and den Hertog, J. (2011) Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects. Disease models & mechanisms. 4(3):393-399.
Abstract
Noonan syndrome is a relatively common developmental disorder that is characterized by reduced growth, wide-set eyes and congenital heart defects. Noonan syndrome is associated with dysregulation of the Ras-mitogen-activated-protein-kinase (MAPK) signaling pathway. Recently, two mutations in NRAS were reported to be associated with Noonan syndrome, T50I and G60E. Here, we report a mutation in NRAS, resulting in an I24N amino acid substitution, that we identified in an individual bearing typical Noonan syndrome features. The I24N mutation activates N-Ras, resulting in enhanced downstream signaling. Expression of N-Ras-I24N, N-Ras-G60E or the strongly activating mutant N-Ras-G12V, which we included as a positive control, results in developmental defects in zebrafish embryos, demonstrating that these activating N-Ras mutants are sufficient to induce developmental disorders. The defects in zebrafish embryos are reminiscent of symptoms in individuals with Noonan syndrome and phenocopy the defects that other Noonan-syndrome-associated genes induce in zebrafish embryos. MEK inhibition completely rescued the activated N-Ras-induced phenotypes, demonstrating that these defects are mediated exclusively by Ras-MAPK signaling. In conclusion, mutations in NRAS from individuals with Noonan syndrome activated N-Ras signaling and induced developmental defects in zebrafish embryos, indicating that activating mutations in NRAS cause Noonan syndrome.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping